SMAD4 – Hereditary Hemorrhagic Telangiectasia

Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant vascular dysplasia characterised by recurrent epistaxis, mucocutaneous telangiectasia, and visceral arteriovenous malformations (PMID:15031030). While most HHT cases are due to ENG or ACVRL1 mutations, heterozygous loss-of-function variants in SMAD4 also underlie an overlapping syndrome of juvenile polyposis (JPS) and HHT (JP-HHT).

In ClinGen terms, the SMAD4–HHT association is Definitive: seven unrelated families with cosegregating LoF mutations including three de novo events and transmission to affected offspring (PMID:15031030); additional segregation in multiple family members across independent pedigrees.

SMAD4-related HHT exhibits autosomal dominant inheritance. Segregation analysis across seven pedigrees identified at least 14 affected relatives with segregating SMAD4 variants. A spectrum of loss-of-function alleles (nonsense, frameshift, splice) and rare missense changes has been reported. Notably, the recurrent truncating variant c.1245_1248del (p.Asp415GlufsTer20) was found in multiple JP-HHT patients with HHT features including asymptomatic pulmonary and cerebral arteriovenous malformations (PMID:23239472).

Functional studies support a Moderate tier of evidence: SMAD4 encodes the common mediator in TGF-β signalling, and haploinsufficiency disrupts vascular homeostasis. In JP-HHT AVM tissue, biallelic loss of SMAD4 via a second-hit somatic mutation (c.350dup, p.Tyr117Ter) plus loss of heterozygosity confirms a two-hit pathogenesis in vascular lesions (PMID:39939156). Smad4 knockout models further demonstrate requirements for mesoderm and vascular development, mirroring human phenotype.

A Disputed locus (HHT3) on chromosome 5 lacking SMAD4 mutations highlights genetic heterogeneity and suggests that not all HHT families harbour SMAD4 variants (PMID:15994879).

Integrating genetic and functional data, SMAD4 loss-of-function is conclusively implicated in HHT-JPS overlap and isolated HHT, guiding diagnostic gene panels, family screening for AVMs and polyposis, and risk assessment for thoracic aortic disease. Key take-home: SMAD4 mutation carriers benefit from combined vascular and gastrointestinal surveillance to mitigate serious complications.

References

• Lancet • 2004 • A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4). PMID:15031030
• Thorax • 2010 • SMAD4 mutation and the combined syndrome of juvenile polyposis syndrome and hereditary haemorrhagic telangiectasia. PMID:20685751
• American Journal of Medical Genetics Part A • 2013 • Thoracic aortic disease in two patients with juvenile polyposis syndrome and SMAD4 mutations. PMID:23239472
• Journal of Medical Genetics • 2025 • Arteriovenous malformation from a patient with JP-HHT harbours two second-hit somatic DNA alterations in SMAD4. PMID:39939156
• Journal of Medical Genetics • 2005 • A new locus for hereditary haemorrhagic telangiectasia (HHT3) maps to chromosome 5. PMID:15994879

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